Series of Compounds for Treatment of Skin Diseases and Other Conditions

ABSTRACT

Compounds and methods related to the prevention and treatment of diseases and conditions, some of which are facilitated by melanogenesis are disclosed. Specifically, the present subject matter includes a series of compounds and compositions and their use for anti-melanogenic and antioxidant activity. This subject matter also includes the treatment of skin disorder due to acne vulgaris and related inflammatory and post inflammatory hyperpigmentation. Methods for synthesizing contemplated compounds are also disclosed.

This United States Utility Application claims priority to U.S.Provisional Application Ser. No. 62/745380 entitled “A Series of NovelCompounds for Treatment of Acne Vulgaris, Inflammation, and SkinDisorders”, which was filed on Oct. 14, 2018, which is commonly-ownedand which is incorporated by reference in its entirety.

FIELD OF THE SUBJECT MATTER

This subject matter generally relates to the prevention and treatment ofdiseases and conditions, some of which are facilitated by melanogenesis.Specifically, the present subject matter includes a series of compoundsand compositions and their use for anti-melanogenic and antioxidantactivity. This subject matter also includes the treatment of skindisorder due to acne vulgaris and related inflammatory and postinflammatory hyperpigmentation. Further included in the present subjectmatter are methods for synthesizing these compounds.

BACKGROUND

There is a great demand for materials able to inhibit or preventexcessive pigmentation of the skin. Melanin, the skin's natural pigment,is a nitrogenous polymer synthesized in melanosomes, which aremembrane-bound organelle present within melanocytes. Melanin is producedin varying concentrations, depending on skin type (genetic disposition)and environmental conditions. Melanocytes are melanin producing cellsthat occur in the basal membrane of the epidermis, hair follicles, eyes,inner ear, bones, heart and brain of humans. When stimulated, by factorssuch as ultraviolet (UV) light melanocytes divide more rapidly, therebyproducing greater quantities of melanin. The melanin is then transportedin mature melanosomes to keratinocytes, within the epidermis where itbecomes visible as a skin color varying from brown to black (eumelanin)and red to yellow (pheomelanin) (Prota G. Med. Res. Rev. 1988, 8,525-556). In human skin, melanin is believed to act as a protectiveagent against ultraviolet radiation. As such, people living close toequator have darker skin than those living in areas away from theequator. Overproduction of melanin can cause different types of abnormalskin color, hair color, and other dermatological disorders, such asmelasma, age spots and sites of actinic damage (Seiberg et al. (2000) J.Invest. Dermatol. 115:162; Paine et al. (2001) J. Invest. Dermatol.116:587).

Modulators of melanogenesis (the production of melanin) may be designedor chosen to function in a variety of ways as illustrated in Prior ArtFIG. 1. With reference to Prior Art FIG. 1, the two types of melanin,eumelanin and pheomelanin are synthesized in response to externalsignals which activate signaling cascades and result in the activationof the MITF transcription factor and the production of downstream geneproducts, including enzymes which are directly involved inmelanogenesis. Activation of the PKC (brown), cAMP (blue), MEK (purple),or WNT (orange) pathways by ligand binding through KIT, MC1R, or otherreceptors at the melanocyte cell surface drives activation of MITF.Upregulation of melanogenesis-related genes enable production of melaninin the melanosome, a membrane-bound vesicle.

Melanin is produced from precursors by the tyrosinase enzyme for whichthere is a strict requirement. Human tyrosinase has two distinctactivities: tyrosine hydroxylation, which catalyzes the conversion oftyrosine to L-DOPA, and DOPA oxidation, which catalyzes the conversionof L-DOPA to dopaquinone. Both steps are required for eumelaninproduction from tyrosine. Phenylalanine hydroxylase catalyzes theproduction of tyrosine from phenylalanine, if additional tyrosinesubstrate is required. Additional enzymes, Tyrosinase-related protein 1(TRP1) and Tyrosinase-related protein 2 (TRP2), carry out theconversions of downstream effectors to eumelanin.

In melanocytes, regulation of melanogenesis occurs at several levels.Tyrosinase and other melanogenesis-related proteins, such as TRP1 andPMEL17, premelanosome protein 17, are regulated at the gene expressionlevel by MITF, the microphthalmia-associated transcription factor.Activation of MITF increases expression of these genes and consequently,increases melanin production. Activation status of MITF is regulated bydownstream kinases from the cAMP, MEK, PI3K, and Wnt pathways, which areregulated at the cell surface by ligands binding to receptors. Kitreceptor is activated by its ligand, SCF, stem cell factor, and MC1R isactivated by either a-MSH, alpha melanocyte stimulating hormone, orACTH, adrenocorticotropic hormone. Ligand binding at these receptors, orothers involved in these signaling cascades, results in activation ofkinase signaling pathways and downstream activation of MITF,upregulation of melanogenic genes, and production of melanin.

There is also a structural component to melanogenesis regulation. Withinmelanosomes themselves, the reactions in the melanogenic pathway largelyoccur on scaffolds of PMEL17, a glycoprotein that binds melaninintermediate products and allows for targeted catalysis by melanogenicenzymes, tyrosinase, TRP1, and TRP2. PMEL17 is itself a membrane-boundglycoprotein until it is processed within the melanosome into a solubleprotein by BACE-2, Beta-site APP Cleaving Enzyme-2, γ-secretase,pro-protein convertase, and metalloproteinase. Once soluble, PMEL17forms fibrils which sequester melanin precursors to allow for increasedaccess by catalytic enzymes. MART-1, Melanoma-associated antigenrecognized by T-cells, or Melan-A, interacts with PMEL17 and is criticalfor PMEL17 expression and function.

Melanosomes containing mature melanin are transported from melanocytesto keratinocytes to disperse pigment throughout the skin tissue. Thisoccurs due to clathrin-coated vesicle transport machinery, including RabG-proteins, SNAREs, and clathrin coat proteins. Uptake by thekeratinocytes requires PAR-2.

Disruption of melanogenesis occurs through the disruption of melaninproduction itself through inhibition of one of the melanogenic enzymes,inhibition of enzyme production, increased degradation of enzymes,inhibition of structural scaffolds affiliated with melanogenesis ormelanosome biosynthesis, or inhibition of melanosome transport. Thecompounds included in this subject matter are anti-melanogenic due todisruption of melanogenesis through one or more of these mechanisms.

This subject matter also includes the treatment of skin disorder due toacne vulgaris and related inflammatory and post inflammatoryhyperpigmentation. Acne vulgaris is multifactorial disease, involvinghyperkeratinization, hormonal function, bacterial proliferation, andimmune hypersensitivity. It is common and affects nearly all teenagersand adults at some time in their lives. Acne generally occurs within thehair follicle. At the base of hair follicle, sebaceous glands aresituated which produces sebum. In a healthy skin, the sebaceous glandproduces the appropriate amount of sebum to maintain the health of thesurrounding skin, and the sebum is efficiently extruded along with thehair. However, excessive growth of the sebaceous glands (sebaceoushyperplasia) and overproduction of sebum can be an important contributorto acne symptoms. Sebaceous hyperplasia can be triggered by increases inandrogen hormones which tends to peak in the mid-teenage years and isconsidered a prime factor in initiating acne. The androgenic hormones(sex hormones) are secreted in the body and enter into the sebaceousgland, where the enzyme 5-alpha reductase converts the testosterone intodi-hydrotestosterone; this in turn stimulates sebum formation in thesebaceous glands.

As a result of hyperactivity of sebaceous gland, excess sebum mixed withdried skin that clogged the follicle. When pores are clogged, acnebacteria have a way of “breaking out” of the pore so their descendantscan go to live in another pore. They release chemicals that sensitizeskin cells to the immune system.

Many of the components made by the bacteria are easily recognized by theimmune system as “foreign” molecules which induce immune cells tosecrete several proinflammatory cytokines, such as TNF-α, (IL)-8, andIL-1β, and activate inflammatory pathways involving the activity ofenzymes such as COX-1, COX-2, 5-LOX, that are important for thedevelopment of skin inflammation.

When the immune system attacks the bacteria, it also kills healthy skincells. This reddens and inflames the skin, and at some point, somebacteria will escape when the pimple bursts open. While the breakout isstill healing, these spots might start off as purple or red beforefading into a darker tone of the surrounding skin. Post inflammatoryhyperpigmentation (PIH) is a unique skin pigmentation condition thatinvolves increased melanin synthesis and deposition. Human skin containsspecialized cells, called melanocytes, which are located at the base ofthe epidermis. These cells are programmed to manufacture a pigment,called melanin, in response to damage and in an attempt to protect orheal itself. PIH is also characterized by apoptosis of melanocyte cellsdue to oxidative stress and assaults from mediators and cytokines ofinflammatory and immune responses. The melanin deposition (i.e.,hyperpigmentation) occurs beyond the epidermal level, with significantmelanin being released into the papillary dermis and trapped by largeimmune cells. These unique histological characteristics of PIH present anumber of difficulties for treatment with traditional agents.

Topical antimicrobials, including benzoyl peroxide and antibiotics, areeffective in treating inflammatory disease. Benzoyl peroxide is abactericidal agent that prevents the resistance of P. acnes toantibiotic therapy and has moderate comedolytic and anti-inflammatoryproperties. It is available in various topical preparations, ranging instrength from 2.5% to 10.0%. Any strength can be used initially,although it may be more prudent to start with a lower concentration;stronger preparations are more irritating and not necessarily moreeffective. Benzoyl peroxide kills P. acnes by releasing oxygen withinthe follicle. It can be fast-acting, with a response as early as fivedays. The main drawback is that it is a potent bleaching agent. Patientsshould be warned that fabrics that come in contact with benzoylperoxide, including towels, bed sheets and clothing, may be bleached.

Topical erythromycin and clindamycin are generally well-tolerated andhave been shown to reduce inflammatory lesions by 46% to 70% in severalrandomized controlled trials. Monotherapy with topical antibioticsshould not be used routinely because P. acnes may become resistantwithin one month after daily treatment has begun. Some argue that thisresistance is not relevant because the antibiotics (e.g., clindamycin,tetracyclines, erythromycin) also have intrinsic anti-inflammatory andantimicrobial effects. However, antibiotic-resistant Staphylococcusepidermidis and Staphylococcus aureus may also develop with monotherapy;resistance can be avoided when a topical antibiotic is combined withbenzoyl peroxide. Combination therapy, for example with retinoids andantibiotics, is more effective than either agent used alone. However,the agents should be applied at separate times, unless they are known tobe compatible. Benzoyl peroxide may oxidize retinoids, such astretinoin, if applied simultaneously. A 12-week randomized controlledtrial involving 249 patients with mild to moderate acne showed treatmentwith adapalene gel 0.1% and clindamycin 1.0% to be superior to that withclindamycin 1.0% used alone. If inflammatory lesions are present,topical antibiotics containing benzoyl peroxide should be combined witha topical retinoid (e.g., topical antibiotic with benzoyl peroxide inthe morning and retinoid at night). A review of three clinical studieswith 1259 patients showed that a combination of clindamycin 1% andbenzoyl peroxide 5% was more effective than either drug used alone inreducing lesions and suppressing P. acnes.

Common treatments for PIH are focused on prevention of further pigmentdevelopment by controlling inflammation with corticosteroids and usingphotoprotection agents. Chemical peeling compounds, such as salicylicacid and glycolic acid, are also used to facilitate the skin renewalfunction and to remove or diminish the pigmentation. Topical retinoidshave also been used to treat PIH, but such methods require up to 40weeks before significant benefits are seen.

Tyrosinase inhibitors, or skin whiteners, such as hydroquinone, azelaicacid, kojic acid and licorice extract, have also been employed fortreatment of PIH. One significant disadvantage of using traditional skinwhitening agents or tyrosinase inhibitors is the non-specificdiscoloration of the regular skin near the PIH site. This effect reducesthe color of the background skin and makes the PIH sites more prominent.Thus, these agents must be applied very carefully over the site of thePIH. In addition, tyrosinase inhibitors are only effective for epidermalhyperpigmentation since this is the location of melanin synthesis bytyrosinase. Because post inflammatory pigmentation is in a deep layer ofthe skin (e.g., papillary dermis), it takes more than 6 months ofcontinued application of hydroquinone medication before visual changesof the dark marks are seen. Finally, hydroquinone type skin whiteners ortyrosinase inhibitors are associated with side effects including skinirritation, dryness, teratogenicity and induction of vitilago and skincancers.

Post inflammatory hyperpigmentation can be derived from endogenousinflammatory skin disorders such as acne, atopic dermatitis, allergiccontact dermatitis, incontinent pigmentation, lichen planus, lupuserythematosus, or morphea. Other causes of PIH include exogenousinflammatory stimuli such as mechanical trauma, ionizing and nonionizingradiation, burns, laser therapies and skin infections. Currenttherapeutic agents for the above skin disorders are ineffective forpreventing, alleviating, reducing or treating PIH. For example, theabove skin disorders are often treated with anti-inflammatory agents,such as retinoids, COX inhibitors (e.g., salicylic acid), nonsteroidalanti-inflammatory drugs (NSAIDs), antimicrobial agents or hormonaldrugs, but these treatments have been shown to be ineffective againstPIH.

While significant advances have been made in the field of skin care andmany compounds have been reported from natural as well as syntheticsources as potent tyrosinase inhibitors with anti-melanogenic activity,very few of them have shown to be effective skin whiteners. Most ofthese agents were found either toxic or shown to have adverse sideeffects in humans. Additionally, many compounds have been reported asstrong anti-melanogenic or antimicrobial or anti-inflammatory to inhibitPIH, none of them has quadruple actions. As such, there continues to bea need in the art for methods for preventing, alleviating, reducing ortreating melanogenic, acne vulgaris, inflammation and excesspigmentation having a single compound possess quadruple actions. Thepresent subject matter fulfills these needs and provides further relatedadvantages.

SUMMARY OF THE SUBJECT MATTER

Compounds of formula I are described herein:

wherein R comprises an aromatic or heteroaromatic ring selected from thegroup consisting of phenyl, naphthyl, biphenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-furanyl, 3-furanyl; wherein R is substituted with 1 to 3moieties (R′, R″, R′″) independently selected from the group consistingof a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group or a hydroxyl group.

Compounds of formula II are described herein:

wherein R comprises an aromatic or heteroaromatic ring selected from thegroup consisting of phenyl, naphthyl, biphenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-furanyl, 3-furanyl; wherein R is substituted with 1 to 3moieties (R′, R″, R′″) independently selected from the group consistingof a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group or a hydroxyl group.

Compounds of formula III are described herein:

wherein R comprises an aromatic or heteroaromatic ring selected from thegroup consisting of phenyl, naphthyl, biphenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-furanyl, 3-furanyl; wherein R is substituted with 1 to 3moieties (R′, R″, R′″) independently selected from the group consistingof a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group or a hydroxyl group.

Compositions comprising (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol(1); (E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof are disclosedherein alone or in combination with one another.

Methods for inhibiting the production of melanin are disclosedcomprising administering to a subject in need thereof a compositioncomprising at least one of the following compounds:(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1, 5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for preventing and treating diseases and conditions related tothe overproduction or uneven distribution of melanin comprisingadministering to a subject in need thereof an effective amount of acomposition are disclosed herein comprising at least one of thefollowing compounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for whitening and/or lightening skin comprising administering toa subject in need thereof a composition are disclosed herein comprisingat least one of the following compounds:(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for preventing melanin synthesis wherein the symptom, condition,disorder, or disease associated tyrosinase inhibition comprisingadministering to a subject in need thereof an effective amount of acomposition are disclosed herein comprising at least one of thefollowing compounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for preventing melanin synthesis wherein the symptom, condition,disorder, or disease associated non-tyrosinase inhibition comprisingadministering to a subject in need thereof an effective amount of acomposition are disclosed herein comprising at least one of thefollowing compounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for preventing and treating diseases wherein the symptom,condition, disorder, or disease associated with free radicals, oxidativestress, UV rays induced skin damages, skin aging, skin inflammatorydiseases or disorders, skin degenerative diseases or disorderscomprising administering to a subject in need thereof an effectiveamount of a composition are disclosed herein comprising at least one ofthe following compounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol(1); (E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for inhibit the browning and color changes in fruits,vegetables, juices and other food products comprising administering acompound are disclosed herein comprising at least one of the followingcompounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for suppressing the activity of Propionibacterium (p-acnes)comprising administering to a patient in need thereof a composition aredisclosed herein comprising at least one the following compounds:(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for deactivating the activity of proinflammatory cytokines, suchas COX-1, COX-2, and 5-LOX comprising administering to a patient in needthereof a composition are disclosed herein comprising at least one ofthe following compounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol(1); (E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10); (E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide (11);(E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE FIGURES

Prior Art FIG. 1 shows that the two types of melanin, eumelanin andpheomelanin, are synthesized in response to external signals whichactivate signaling cascades and result in the activation of the MITFtranscription factor and the production of downstream gene products,including enzymes which are directly involved in melanogenesis.Activation of the PKC (brown), cAMP (blue), MEK (purple), or WNT(orange) pathways by ligand binding through KIT, MC1R, or otherreceptors at the melanocyte cell surface drives activation of MITF.Upregulation of melanogenesis-related genes enable production of melaninin the melanosome, a membrane-bound vesicle. Melanin is produced fromprecursors by the tyrosinase enzyme for which there is a strictrequirement.

FIG. 2 illustrates graphically a profile of the inhibition in theproduction of melanin by (E/Z)-4-(2,6-Dimethylhepta-1,5-dienyl)phenol(1) as described in Example 5. The data is presented as melanin content(% of untreated control) vs. inhibitor concentration (μM). The IC50 ofcompound 1 was determined to be 158 μM. FIG. 2 also illustratesgraphically cell viability at varying concentrations of compound 1. TheLD₅₀ for compound 1 was determined to be 269 μM.

FIG. 3 illustrates graphically a profile of the inhibition in theproduction of melanin by(E/Z)-5-(2,6-Dimethylhepta-1,5-dienyl)benzene-1,3-diol (4) as describedin Example 5. The data is presented as melanin content (% of untreatedcontrol) vs. inhibitor concentration (μM). The IC₅₀ of compound 4 wasdetermined to be 72 ρM. FIG. 3 also illustrates graphically cellviability (LD₅₀) at varying concentrations of compound 4. The LD₅₀ forcompound 15 was determined to be 127 μM.

FIG. 4 illustrates graphically a profile of the inhibition in theproduction of melanin by (E)-4-(3,7-Dimethylocta-1,6-dienyl)benzene-1,3-diol (6) as described in Example 5. The data is presented asmelanin content (% of untreated control) vs. inhibitor concentration(μM). The IC₅₀ of compound 6 was determined to be 9 μM. FIG. 4 alsoillustrates graphically cell viability (LD₅₀) at varying concentrationsof compound 6. The LD50 for compound 6 was determined to be 233 μM.

FIG. 5 illustrates graphically a profile of the inhibition in theproduction of melanin by (E)-5-(3,7-Dimethylocta-1,6-dienyl)benzene-1,3-diol (7) as described in Example 5. The data is presented asmelanin content (% of untreated control) vs. inhibitor concentration(μM). The IC₅₀ of compound 7 was determined to be 97 μM. FIG. 5 alsoillustrates graphically cell viability (LD₅₀) at varying concentrationsof compound 7. The LD₅₀ for compound 7 was determined to be 152 μM.

FIG. 6 illustrates graphically a profile of the inhibition in theproduction of melanin by (E)-6-(3,7-Dimethylocta-1,6-dienyl)naphthalene-2-ol (8) as described in Example 5. The data is presented asmelanin content (% of untreated control) vs. inhibitor concentration(μM). The IC₅₀ of compound 8 was determined to be 22 μM. FIG. 6 alsoillustrates graphically cell viability (LD₅₀) at varying concentrationsof compound 8. The LD₅₀ for compound 8 was determined to be 68 μM.

FIG. 7 illustrates graphically a profile of the inhibition in theproduction of melanin by (E)-3-(3,7-Dimethylocta-1,6-dienyl) pyridine(12) as described in Example 5. The data is presented as melanin content(% of untreated control) vs. inhibitor concentration (μM). The IC₅₀ ofcompound 12 was determined to be 74 μM. FIG. 7 also illustratesgraphically cell viability (LD₅₀) at varying concentrations of compound12. The LD₅₀ for compound 12 was determined to be 385 μM.

FIG. 8 illustrates graphically a profile of the inhibition in theproduction of melanin by (Z)-5-(4,8-Dimethylnona-1,7-dienyl)benzene-1,3-diol (15) as described in Example 5. The data is presentedas melanin content (% of untreated control) vs. inhibitor concentration(μM). The IC₅₀ of compound 15 was determined to be 74 μM. FIG. 8 alsoillustrates graphically cell viability (LD₅₀) at varying concentrationsof compound 15. The LD₅₀ for compound 15 was determined to be 145 μM.

FIG. 9 graphically depicts the mushroom tyrosinase inhibition ofcompound 6 in an in vitro enzymatic inhibition assay as described inExample 4. There is defined dose-dependent inhibition of the tyrosinaseenzyme by compound 6 with an IC₅₀ of 20 μM.

FIG. 10A depicts the melanin inhibition of compound 1 on reconstructedskin prepared as described in Example 6. The reconstructed skin wasgrown at the air-liquid interface, making it possible to mimic topicalapplication of skin whitening agents. The reconstructed skin containedboth keratinocytes and melanocytes.

FIG. 10B depicts photographically the results of the reconstructed skinstudies utilizing compound 1 as described in Example 6. Photographs ofskin specimen taken after 14 days of the experiment show significantwhitening effects on melanocytes, which appear on photographs as darkdendritic cells.

FIG. 11A depicts the melanin inhibition of compound 4 on reconstructedskin prepared as described in Example 6. The reconstructed skin wasgrown at the air-liquid interface, making it possible to mimic topicalapplication of skin whitening agents. The reconstructed skin containedboth keratinocytes and melanocytes. At 0.05%, compound 4 showed sometoxicity.

FIG. 11B depicts photographically the results of the reconstructed skinstudies utilizing compound 4 as described in Example 6. Photographs ofskin specimen taken after 14 days of the experiment show significantwhitening effects on melanocytes, which appear on photographs as darkdendritic cells. At 0.05%, compound 4 showed some toxicity.

FIG. 12A depicts the melanin inhibition of compound 6 on reconstructedskin prepared as described in Example 6. The reconstructed skin wasgrown at the air-liquid interface, making it possible to mimic topicalapplication of skin whitening agents. The reconstructed skin containedboth keratinocytes and melanocytes.

FIG. 12B depicts photographically the results of the reconstructed skinstudies utilizing compound 6 as described in Example 6. Photographs ofskin specimen taken after 14 days of the experiment show significantwhitening effects on melanocytes, which appear on photographs as darkdendritic cells.

FIG. 13A depicts the melanin inhibition of compound 7 on reconstructedskin prepared as described in Example 6. The reconstructed skin wasgrown at the air-liquid interface, making it possible to mimic topicalapplication of skin whitening agents. The reconstructed skin containedboth keratinocytes and melanocytes. At 0.05%, compound 7 showed sometoxicity.

FIG. 13B depicts photographically the results of the reconstructed skinstudies utilizing compound 7 as described in Example 6. Photographs ofskin specimen taken after 14 days of the experiment show significantwhitening effects on melanocytes, which appear on photographs as darkdendritic cells. At 0.05%, compound 7 showed some toxicity.

FIG. 14A depicts the melanin inhibition of compound 8 on reconstructedskin prepared as described in Example 6. The reconstructed skin wasgrown at the air-liquid interface, making it possible to mimic topicalapplication of skin whitening agents. The reconstructed skin containedboth keratinocytes and melanocytes. At 0.05%, compound 8 showed sometoxicity.

FIG. 15A depicts the melanin inhibition of compound 12 on reconstructedskin prepared as described in Example 6. The reconstructed skin wasgrown at the air-liquid interface, making it possible to mimic topicalapplication of skin whitening agents. The reconstructed skin containedboth keratinocytes and melanocytes. At 0.05%, compound 12 showed sometoxicity.

FIG. 15B depicts photographically the results of the reconstructed skinstudies utilizing compound 12 as described in Example 6. Photographs ofskin specimen taken after 14 days of the experiment show significantwhitening effects on melanocytes, which appear on photographs as darkdendritic cells. At 0.05%, compound 12 showed some toxicity.

FIG. 16A depicts the melanin inhibition of compound 15 on reconstructedskin prepared as described in Example 6. The reconstructed skin wasgrown at the air-liquid interface, making it possible to mimic topicalapplication of skin whitening agents. The reconstructed skin containedboth keratinocytes and melanocytes. At 0.05%, compound 15 showed sometoxicity.

FIG. 16B depicts photographically the results of the reconstructed skinstudies utilizing compound 15 as described in Example 6. Photographs ofskin specimen taken after 14 days of the experiment show significantwhitening effects on melanocytes, which appear on photographs as darkdendritic cells. At 0.05%, compound 15 showed some toxicity.

DETAILED DESCRIPTION

The present disclosure provides pharmaceutical agents that have stronganti-melanogenic activity. The anti-melanogenic properties ofrepresentative compounds were evaluated by means of mushroom tyrosinaseassay, inhibition of melanin production by murine B16-F1 melanoma celland melanin inhibition in a reconstructed human skin model.Specifically, these compounds show inhibition of melanin production bymurine B16-F1 melanoma cells as well as melanin inhibition in thereconstructed human skin model, but they show poor inhibitory activityon mushroom tyrosinase enzyme. This finding suggests that the activeingredients affect the modulators in one of the melanogenic signalingpathways (Prior Art FIG. 1), which has the end result of reducing themelanin in the tissue. This anti-melanogenic activity may be due toinhibition of other enzymes in melanogenesis, increased degradation orreduced expression of melanogenic enzymes, inhibition of othercomponents of the melanogenesis signaling pathways, inhibition ofstructural proteins involved in melanogenesis, or decreased melanosometransport. Contemplated embodiments treat melanin-producing cells witheach compound and measure global gene expression changes to determinewhich pathways are affected to ascertain the mechanism of action.

In addition, the present subject matter also possesses superiorantimicrobial activity against propionibacterium (p-acne) as well aspotent inhibition of proinflammatory cytokines including COX-1, COX-2and 5-LOX.

The strong antimicrobial properties of a representative compound wereevaluated by MIC/MBC test against propionibacterium (p-acne). Theanti-inflammation properties were evaluated by inhibitory assay againstproinflammatory enzymes including COX-1, COX-2 and 5-LOX.

Compounds of formula I are described herein:

wherein R comprises an aromatic or heteroaromatic ring selected from thegroup consisting of phenyl, naphthyl, biphenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-furanyl, 3-furanyl; wherein R is substituted with 1 to 3moieties (R′, R″, R′″) independently selected from the group consistingof a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group or a hydroxyl group.

Compounds of formula II are described herein:

wherein R comprises an aromatic or heteroaromatic ring selected from thegroup consisting of phenyl, naphthyl, biphenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-furanyl, 3-furanyl; wherein R is substituted with 1 to 3moieties (R′, R″, R′″) independently selected from the group consistingof a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group or a hydroxyl group.

Compounds of formula III are described herein:

wherein R comprises an aromatic or heteroaromatic ring selected from thegroup consisting of phenyl, naphthyl, biphenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-furanyl, 3-furanyl; wherein R is substituted with 1 to 3moieties (R′, R″, R′″) independently selected from the group consistingof a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group or a hydroxyl group.

Compositions comprising (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol(1); (E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof are disclosedherein alone or in combination with one another.

Methods for inhibiting the production of melanin are disclosedcomprising administering to a subject in need thereof a compositioncomprising at least one of the following compounds:(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1, 5-dienyl)benzene-1, 3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for preventing and treating diseases and conditions related tothe overproduction or uneven distribution of melanin comprisingadministering to a subject in need thereof an effective amount of acomposition are disclosed herein comprising at least one of thefollowing compounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for whitening and/or lightening skin comprising administering toa subject in need thereof a composition are disclosed herein comprisingat least one of the following compounds:(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for preventing melanin synthesis wherein the symptom, condition,disorder, or disease associated tyrosinase inhibition comprisingadministering to a subject in need thereof an effective amount of acomposition are disclosed herein comprising at least one of thefollowing compounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for preventing melanin synthesis wherein the symptom, condition,disorder, or disease associated non-tyrosinase inhibition comprisingadministering to a subject in need thereof an effective amount of acomposition are disclosed herein comprising at least one of thefollowing compounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for preventing and treating diseases wherein the symptom,condition, disorder, or disease associated with free radicals, oxidativestress, UV rays induced skin damages, skin aging, skin inflammatorydiseases or disorders, skin degenerative diseases or disorderscomprising administering to a subject in need thereof an effectiveamount of a composition are disclosed herein comprising at least one ofthe following compounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol(1); (E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1, 5-dienyl)benzene-1, 3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for inhibit the browning and color changes in fruits,vegetables, juices and other food products comprising administering acompound are disclosed herein comprising at least one of the followingcompounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide (11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for suppressing the activity of Propionibacterium (p-acnes)comprising administering to a patient in need thereof a composition aredisclosed herein comprising at least one the following compounds:(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

Methods for deactivating the activity of proinflammatory cytokines, suchas COX-1, COX-2, and 5-LOX comprising administering to a patient in needthereof a composition are disclosed herein comprising at least one ofthe following compounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol(1); (E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10); (E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetam ide (11);(E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.

These before mentioned methods are contemplated to be effective withdiseases and conditions that comprise, and in some instances consist of,suntan, hyper pigmentation spots caused by skin aging, melasma, liverdiseases, thermal burns and topical wounds, skin pigmentation due toinflammatory conditions caused by fungal, microbial and viralinfections, vitiligo, carcinoma, melanoma, as well as other mammalianskin conditions.

In some embodiments, these methods are contemplated effective with postinflammatory hyperpigmentation (PIH) that is derived from acne, atopicdermatitis, allergic contact dermatitis, incontinent pigmentation,lichen planus, lupus erythematosus, morphea, mechanical trauma, ionizingor nonionizing radiation, burns, laser or drug therapies, skin infectionor combinations thereof.

The present subject matter also includes a novel composition of mattercomprised of dienes, wherein said dienes are selected from the group ofcompounds represented by the following general structure:

Wherein, “Ar” the term “aromatic” as used herein refers to any compoundwhich includes or consists of one or more hydrocarbon aromatic rings.The rings may be mono or polycyclic ring systems. Examples of suitablerings include, but are not limited to benzene, naphthalene, biphenyl,terphenyl etc. Ar is independently selected from the group consisting ofa substituted 5- or 6-membered aromatic or heteroaromatic ring, whereineach 6-membered aromatic or heteroaromatic ring is independentlysubstituted with 1-5 R′ groups consisting of —H, —OH, —SH, —OR, —CN,—SR, —NH₂, —NHR, —NR₂, X, Wherein, X is a halogen, selected from thegroup consisting of Cl, Br, F, I; R₁₋₈, are independently selected fromthe group consisting of —H, an alkyl, alkenyl group can be substitutedor optionally unsubstituted with one or more substituents having between1-20 carbon atoms, and n=0 to 5. In a preferred embodiment n=0-2.

In one contemplated embodiment, said dienes are selected from the groupof compounds represented by the following general structure:

Wherein, R₁₋₈, are independently selected from the group consisting of—H, an alkyl, alkenyl group can be substituted or optionallyunsubstituted with one or more substituents having between 1-20 carbonatoms, and n=0 to 5. In a preferred embodiment n=0-2.

In a contemplated embodiment, the present disclosure providespharmaceuticals and cosmeceuticals agent that are depicted in FormulaI-III. These compounds or their pharmaceutically acceptable salts, notlimited to racemic version, but also apply to single enantiomer withpreferred position. These compounds or their pharmaceutically acceptablesalts also not only limited to preferred geometrical isomer, either E/orZ, but a mixture in composition.

These compounds or their pharmaceutically acceptable salts thereof areshown to be useful for both cosmeceuticals and pharmaceuticalsapplications.

These compounds also showed anti-melanogenic property with lowcytotoxicity. The anti-melanogenic properties were evaluated by means oftyrosinase inhibitory activity as well as, the inhibition of melaninproduction by murine B16-F1 melanoma cells. Illustrated is theinhibitory activity of representative compounds against mushroomtyrosinase, as well as, the inhibition of melanin production by murineB16-F1 melanoma cells as described in Examples 4 and 5. The skinwhitening properties of representative compounds were evaluated by meansof a reconstructed human skin model as described in Example 6. Thesecompounds or their pharmaceutically acceptable salts thereof are shownto be useful for both cosmetic and medical applications as detailedbelow.

These compounds are shown to have excellent antimicrobial propertyagainst Propionibacterium (p-acne bacterium), a gram-positive bacteria,in single digit ppm level. The antimicrobial properties ofrepresentative compounds were evaluated by means of inhibitory activityagainst p-acnes bacterium described in Example 7.

These compounds also showed excellent anti-inflammatory property againstpost-inflammatory cytokines such as COX-1, COX-2, and 5-LOX. Theantimicrobial properties of representative compounds were evaluated bymeans of inhibitory activity against post-inflammatory cytokines such asCOX-1, COX-2, and 5-LOX as described in Example 8.

As used in this context, the term “derivative” or “analog” refers to acompound having similar chemical structure or function as the compoundsof Formula I-III that retains the core dienes, either 1,5-, 1,6-, or1-7-dienes with substituted aromatic ring.

Various terms are used herein to refer to aspects of the present subjectmatter. To aid in the clarification of the description of the componentsof this subject matter, the following definitions are provided. Unlessdefined otherwise all technical and scientific terms used herein havethe meaning commonly understood by one of ordinary skill in the art towhich this subject matter belongs.

It is to be noted that as used herein the term “a” or “an” entity refersto one or more of that entity; for example, a tyrosinase inhibitorrefers to one or more tyrosinase inhibitors. As such, the terms “a” or“an”, “one or more” and “at least one” are used interchangeably herein.

As used herein, “about” will be understood by persons of ordinary skillin the art and will vary to some extent on the context in which it isused. If there are uses of the term which are not clear to persons ofordinary skill in the art given the context in which it is used, “about”will mean up to plus or minus 10% of the particular term.

The term “dienes” as used herein refers to a straight or branched chain,unsaturated hydrocarbon having the indicated number of carbon atoms. Forexample, (C1-C10) alkenyl is meant to include a straight or branchedchain hydrocarbon having one to ten carbon atoms. An alkenyl group canbe substituted or optionally unsubstituted with one or more substituentsas described herein.

The term “aromatic” as used herein refers to any compound which includesor consists of one or more hydrocarbon aromatic rings. The rings may bemono or polycyclic ring systems. Examples of suitable rings include, butare not limited to benzene, naphthalene, biphenyl, triphenyl etc.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N) and sulfur (S). The term “heteroaromatic” as used hereinrefers to an aromatic heterocyclic ring of 5 to 14 members and having atleast one heteroatom selected from nitrogen, oxygen and sulfur, andcontaining at least 1 carbon atom. Representative heteroaromaticsinclude pyridyl, furyl, thienyl, pyrrolyl and imidazoly] etc. Theheteroary! group can be attached via any heteroatom or carbon atom,where chemically acceptable. A heteroaryl group can be unsubstituted oroptionally substituted with one or more substituents as describedherein.

As used herein, the term “heterocycle” refers to non-aromatic 5 to14-membered ring systems which are either saturated, unsaturated andwhich contain from 1 to 4 heteroatoms independently selected fromnitrogen, oxygen and sulfur, and wherein the nitrogen and sulfurheteroatoms can be optionally oxidized, and the nitrogen heteroatom canbe optionally quaternized. The heterocycle can be attached via anyheteroatom or carbon atom, where chemically acceptable. Representativeexamples of non-aromatic heterocycles include, but are not limited totetrahydrofuranyl, tetrahydropyrrolyl, pyranyl and tetrahydropyrany]etc. A heterocycle group can be unsubstituted or optionally substitutedwith one or more substituents as described herein.

“Therapeutic” as used herein, includes prevention, treatment and/orprophylaxis. When used therapeutic refers to humans as well as otheranimals.

“Pharmaceutically or therapeutically effective dose or amount” refers toa dosage level sufficient to induce a desired biological result. Thatresult may be the alleviation of the signs, symptoms or causes of adisease or any other alteration of biological system that is desired.The precise dosage will vary according to a variety of factors,including but not limited to the age and size of the subject, thedisease and the treatment being effected.

A “host” or “patient” or “subject” is a living mammal, human or animal,for whom therapy is desired. The “host,” “patient” or “subject”generally refers to the recipient of the therapy to be practicedaccording to the method of the subject matter. It should be noted thatthe subject matter described herein may be used for veterinary as wellas human applications and that the term “host” should not be construedin a limiting manner. In the case of veterinary applications, the dosageranges can be determined as described below, taking into account thebody weight of the animal.

As used herein, the term “pharmaceutically acceptable” means approved bya regulatory agency of a federal or a state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals and, more particularly, in humans. The term “carrier” refersto a diluent, adjuvant, excipient, or vehicle with which the therapeuticis administered and includes, but is not limited to, such sterileliquids as water and oils.

A “pharmaceutically acceptable salt” or “salt” of a tyrosinase inhibitoris a product of the disclosed compound that contains an ionic bond andis typically produced by reacting the disclosed compound with either anacid or a base, suitable for administering to a subject. Apharmaceutically acceptable salt can include, but is not limited to,acid addition salts including hydrochlorides, hydrobromides, phosphates,sulphates, hydrogen sulphates, alkylsulphonates, arylsulpho-nates,arylalkylsulfonates. acetates, benzoates, citrates, maleates, fumarates,succinates, lactates, and tartrates; alkali metal cations such as Li,Na, K, alkali earth metal salts such as Mg or Ca, or organic aminesalts.

A “pharmaceutical composition” is a formulation comprising the disclosedcompounds in a form suitable for administration to a subject. Apharmaceutical composition of the subject matter is preferablyformulated to be compatible with its intended route of administration.Examples of routes of administration include, but are not limited to,oral and parenteral, e.g., intravenous, intradermal, subcutaneous,inhalation, topical, transdermal, transmucosal, and rectaladministration.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.Examples of substituents include, but are not limited to C₁-C₁₀ alkyl,hydroxy (—OH), C₁-C₁₀ alkoxy groups. Typically, an aromatic,heteroaromatic or heterocyclic ring will have from 1-3 substituents.

In a contemplated embodiment, the present subject matter provides acompound having a structure shown in Formula I, or a pharmaceuticallyacceptable salt thereof:

Wherein R is selected from a substituted or unsubstituted aromatic,heteroaromatic or heterocyclic ring. In one embodiment R comprises, andin some instances is selected from the group consisting of, asubstituted or unsubstituted: phenyl, biphenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-furanyl, 3-furanyl. In one embodiment R is substituted with1 to 3 moieties (R′, R″, R™) comprises, and in some instances isselected from the group consisting of, a C₁-C₁₀ alkyl group, a C₁-C₁₀alkoxy group or a hydroxyl group. In other embodiments R is selectedfrom the group consisting of 1′-(4′-methoxy)pheny];1′-(2,4-dihydroxy)phenyl; 1′-(3-pyridyl); 1′-(bi-phenyl-4-ol).

In one of its aspects the present subject matter provides a compoundhaving a structure shown in Formula II or a pharmaceutically acceptablesalt thereof

Wherein R comprises, and in some instances is selected from the groupconsisting of, a substituted or unsubstituted: phenyl, biphenyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl. In one embodimentR is substituted with 1 to 3 moieties (R′, R″, R™) independentlycomprising, and in some instances is selected from the group consistingof, a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group or a hydroxyl group. Inother embodiments R comprises, and in some instances is selected fromthe group consisting of, 1′-(4′-methoxy)pheny];1′-(2,4-dihydroxy)phenyl; 1′-(3-pyridyl); 1′-(bi-phenyl-4-ol).

In one contemplated embodiment, the present subject matter provides acompound having a structure shown in Formula III or a pharmaceuticallyacceptable salt thereof.

Wherein R is selected from a substituted or unsubstituted aromatic,heteroaromatic or heterocyclic ring. In one embodiment R comprises, andin some instances is selected from the group consisting of, asubstituted or unsubstituted: phenyl, biphenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-furanyl, 3-furanyl. In one embodiment R is substituted with1 to 3 moieties (R′, R″, R™) independently comprising, and in someinstances is selected from the group consisting of, a C₁-C₁₀ alkylgroup, a C₁-C₁₀ alkoxy group or a hydroxyl group. In other embodiments Ris selected from the group consisting of 1′-(4′-methoxy)pheny];1′-(2,4-dihydroxy)phenyl; 1′-(3-pyridyl); 1′-(bi-phenyl-4-ol).

Table 1 lists representative novel 1,5-dienes analogs of Formula I whichare useful for anti-melanogenic. The synthetic methods that can be usedto prepare each compound, identified in Table 1 are described in detailin Example 1. Supporting 1H- and 13C-NMR data is provided for eachcompound synthesized. In general, the compounds of Formula I can besynthesized from readily available materials using standard organicsynthesis techniques. Further preparation routes may be found in theliterature and relevant art.

TABLE 1 Compounds Representative of Formula: Anti-melanogenic propertyAnti-melanogenic MUSHROOM MELANIN CELL Compound Structure TYROSINASEPRODUCTION VIABILITY (E)-4-(2,6- Dimethylhepta-1,5- dienyl)phenol (1)

Not active 158 μm 269 μm (E)-3-(2,6- Dimethylhepta-1,5- dienyl)phenol(2)

Not active  82 μm  66 μm (E)-4-(2,6- Dimethylhepta-1,5- dienyl)benzene-1,3-diol (3)

Not active 164 μm 172 μm (E)-5-(2,6- Dimethylhepta-1,5- dienyl)benzene-1,3-diol (4)

Not active  72 μm 127 μm

Table 2 lists representative novel 1,6-dienes analogs of Formula IIwhich are useful as anti-melanogenic. The synthetic methods that can beused to prepare each compound, identified in Table 1 are described indetail in Example 2. Supporting 1H- and 13C-NMR data is provided foreach compound synthesized. In general, the compounds of Formula I can besynthesized from readily available materials using standard organicsynthesis techniques. Further preparation routes may be found in theliterature and relevant art.

TABLE 2 Compounds Representative of Formula II: Anti-melanogenicproperty Anti-melanogenic MUSHROOM MELANIN CELL Compound StructureTYROSINASE PRODUCTION VIABILITY (E)-4-(3,7-Dimethylocta-1,6-dienyl)phenol (5)

N/A  72 μm  50 μm (E)-4-(3,7-Dimethylocta-1,6- dienyl) benzene-1,3-diol(6)

 20 μm  9 μm 233 μm (E)-5-(3,7-Dimethylocta-1,6- dienyl)benzene-1,3-diol (7)

492 μm (theoretical)  97 μm 152 μm E)-6-(3,7-Dimethylocta-1,6- dienyl)naphthalene-2-ol (8)

Not active  22 μm  68 μm (E)-2-(4-(3,7-Dimethylocta-1,6-dienyl)phenoxy)acetic acid (9)

NA NA NA (E)-2,2′-(4-(3,7-Dimethylocta- 1,6-dienyl)-1,3-phenylene)bis(oxy)diacetic acid (10)

NA NA NA (E)-2,2′-(4-(3,7-Dimethylocta- 1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide (11)

NA NA NA (E)-3-(3,7-Dimethylocta-1,6- dienyl) pyridine (12)

Not active  74 μm 385 μm (E)-2-(3,7-Dimethylocta-1,6- dienyl) pyridine(13)

Not active 149 μm 650 μm (E)-5-(3,7-Dimethylocta-1,6-dienyl)-2-methoxypyridine (14)

Not active 147 μm 369 μm

Table 3 lists representative novel 1,6-dienes analogs of Formula IIwhich are useful as anti-melanogenic. The synthetic methods that can beused to prepare each compound, identified in Table 3 are described indetail in Example 3. Supporting 1 H- and 13C-NMR data is provided foreach compound synthesized. In general, the compounds of Formula I can besynthesized from readily available materials using standard organicsynthesis techniques. Further preparation routes may be found in theliterature and relevant art.

TABLE 3 Compounds Representative of Formula III: Anti-melanogenicproperty Anti-melanogenic MUSHROOM MELANIN CELL Compound StructureTYROSINASE PRODUCTION VIABILITY (Z)-5-(4,8-Dimethylnona- 1,7-dienyl)benzene-1,3-diol (15)

Not active 158 μm 269 μm (E)-5-(4,8-Dimethylnona- 1,7-dienyl)benzene-1,3- diol (16)

Not active 164 μm 172 μm (E)-2,2′-(5-(4,8- Dimethylnona-1,7-dienyl)-1,3-phenylene)bis (oxy)diacetic acid (17)

Not active  72 μm 127 μm

The antimicrobial activity was determined of the selected compoundsagainst a Gram-positive—Propionibacterium (p-acnes). The MIC and MBCvalues showed (Table 4) that the remarkable inhibition of the bacterialgrowth was shown against the tested organisms.

The anti-inflammatory activity was determined of the selected compoundsagainst a by the COX-1, COX-2, and 5-LOX assays as described in Example5 are also set forth in Table 4. For select compounds of Formula I-III,Table 4 provides IC₅₀, values as determined by the COX-1, COX-2, and5-LOX assays described in Example 5.

TABLE 4 Compounds Representative of Formula I-III: Anti-acne propertyAnti-microbial Anti-inflammatory (p-acne) (IC₅₀) Compound Structure MICMBC COX-1 COX-2 5-LOX (E/Z)-4-(2,6- Dimethylhepta-1,5- dienyl)phenol (1)

<3.9 ppm  <3.9 ppm 122 μm Not active  90 μm (E/Z)-4-(2,6-Dimethylhepta-1,5- dienyl)benzene- 1,3-diol (3)

<3.9 ppm  <3.9 ppm — — — (E/Z)-5-(2,6- Dimethylhepta-1,5-dienyl)benzene-1,3- diol (4)

<3.9 ppm  <3.9 ppm  64 μm 245 μm 317 μm (E)-4-(3,7-Dimethylocta-1,6-dienyl)phenol (5)

  7.8 ppm   15.6 ppm No Inhibition 72 μm  50 μm (E)-4-(3,7-Dimethylocta-1,6-dienyl) benzene-1,3- diol (6)

  3.9 ppm 3.9-31.3 ppm  74 μm 164 μm 307 μm (E)-5-(3,7-Dimethylocta-1,6-dienyl) benzene-1,3- diol (7)

  7.8 ppm 7.8-31.3 ppm  25 μm 135 μm 143 μm E)-6-(3,7-Dimethylocta-1,6-dienyl) naphthalene- 2-ol (8)

<3.9 ppm  <3.9 ppm (E)-3-(3,7-Dimethylocta- 1,6-dienyl) pyridine (12)

<3.9 ppm  <3.9 ppm (Z)-5-(4,8-Dimethylnona- 1,7-dienyl) benzene-1,3-diol (15)

<3.9 ppm  <3.9 ppm 122 μm No Inhibition  90 μm (E)-5-(4,8-Dimethylnona-1,7-dienyl) benzene-1,3- diol (16)

<3.9 ppm  <3.9 ppm (E)-2,2′-(5-(4,8- Dimethylnona-1,7-dienyl)-1,3-phenylene)bis (oxy)diacetic acid (17)

<3.9 ppm  <3.9 ppm MIC: the lowest level of antimicrobial agent thatinhibits growth. MBC: the lowest concentration of an antimicrobial agentrequired to kill a particular Bacterium.

Table 5 lists representative novel 1,6-dienes analogs of Formula I-IIIwhich are useful as anti-oxidant. ORAC 5.0 consists of five types ofORAC assays that evaluate the antioxidant capacity of material againstfive primary reactive oxygen species (ROSs, commonly called “oxygenradicals”) found in humans: peroxyl radical, hydroxyl radical,superoxide anion, singlet oxygen, and peroxynitrile. Trolox is used asreference standard, and the results are expressed as μ mole Trolexequivalency per gram (or milliliter) of a tested material.

Compounds Representative of Formula I-III: Antioxidant property CompoundStructure ORAC (μ mole TE/gram) (E)-5-(2,6-Dimethylhepta-1,5-dienyl)benzene-1,3-diol (4)

22580 (E)-4-(3,7-Dimethylocta-1,6- dienyl)phenol (5)

37643 (E)-4-(3,7-Dimethylocta-1,6- dienyl) benzene-1,3-diol (6)

45869 (E)-5-(3,7-Dimethylocta-1,6- dienyl) benzene-1,3-diol (7)

18196 (Z)-5-(4,8-Dimethylnona- 1,7-dienyl) benzene-1,3-diol (15)

11951

EXAMPLES Example 1: General and Specific Methods for the Synthesis ofCompounds of Formula I

Compounds of Formula I were prepared generally as set forth in Scheme 1,using a substituted benzylphosphonate as R for purposes of illustration.The phosphonate reagents were prepared from the corresponding benzylbromide treated with triethyl phosphite following Arbuzov Reaction.Briefly, the 1,5-dienes compounds of Formula I were prepared by Wittigreaction from the corresponding phosphonate salt with appropriateketone. Then the coupled diene product was treated with methyl magnesiumiodide for demethylation reaction to get the desired phenol dienes.

Representative Procedure for Scheme 1:

Synthesis of (E/Z)-4-(2,6-Dimethylhepta-1,5-dienyl)phenol (1):

General/Typical Procedure for synthesis of phosphonate salt by ArbuzovReaction: A solution of 4-methoxybenzylbromide (20 g, 100 mmol) inP(OEt)₃ (23 mL, 140 mmol) was refluxed for 5 h followed by removal ofbromoethane and excess triethyl phosphite by distillation at reducedpressure. The residue provided 24.5 g (95%) of product which was enoughpure for next step.

General/Typical Procedure for Wittig reaction: To a solution of thephosphonium salt of benzyl bromide (12 g, 46 mmol) and6-methyl-5-hepten-2-one (5.3g, 42 mmol) in anhydrous DMF (50 mL), NaH(60% dispersion in mineral oil, 46 mmol) was added at 0° C. portionwise. The reaction mixture was allowed to stir 0° C. for 1 h, duringwhich time the mixture developed a red color indicating the formation ofylide. After stirring at room temperature for 3 h, the reaction iscomplete. The mixture is diluted with water at 0° C. and the product isextracted with EtOAc. The organic layer is washed with saturated aqueousNaHCO₃ and brine then dried over Na₂SO₄. The solvent is removed underreduced pressure and the yellow residue was passed through a short bedof silica gel eluting with ethyl acetate-hexane (5:95) to yield thecoupled product (9.7 g, 92%) in a ratio of (E/Z: 80:20) as a pale yellowoil.

General/Typical Procedure for demethylation reaction: To a solution (7g, 21.8 mmol) in 10 ml of Et₂O was added a solution of MeMgI (3M) inEt₂O (10.0 ml, 30 mmol). The solvent was removed under reduced pressure,and the residue was heated under argon at 130-140° C. for 10 min. Themixture was cooled to rt, and the reaction was quenched with 10 ml ofsaturated aqueous NH₄CL solution. The product was extracted with EtOAc(3×100 ml). The combined organic phase was washed with brine and driedover Na₂SO₄. The solvent was removed under reduced pressure, and thecrude product was purified by column chromatography (silica gel;AcOEt/hexane 1:10) to afford the title compound (2.6g, 55%).

(E/Z)-4-(2,6-Dimethylhepta-1,5-dienyl)phenol (1): ¹H-NMR (CDCl₃, 500MHz): Major (E): 7.12 (d, 2H, J=10 Hz), 6.79 (d, 2H, J=10 Hz), 6.20(s,IH), 5.18-5.15(m, IH), 2.25-2.14 (m, 4H), 1.84 (s, 3H), 1.71 (s, 3H),1.64 (s, 3H); Minor (Z): 7.08(d, 2H, J=10 Hz), 6.77 (d, 2H, J=10 Hz),6.21(s, IH), 5.13-5.10(m, IH), 2.25-2.14 (m, 4H), 1.87 (s, 3H), 1.68 (s,3H), 1.61 (s, 3H). ¹³C-NMR (CDCl3, 125 MHz): 153.66 (C), 138.71 (C),131.92 (C), 131.61 (C), 130.21 (CH), 129.96(2CH), 124.21 (CH), 115.08 (2CH), 40.89 (CH₂), 26.95 (CH₂), 25.83 (CH₃) 17.92 (CH₃), 17.81(CH₃).

Representative compounds 2-4 of Formula I (Table 1) were synthesizedaccording to the same general reaction scheme using the appropriatestaring materials. Overall yields varied from 30-48%.

(E/Z)-4-(2,6-Dimethylhepta-1,5-dienyl)benzene-1,3-diol (2): ¹H-NMR(CDCl₃, 500 MHz): 7.16 (d, IH, J=7.5 Hz), 6.78 (d, 2H, J=8 Hz), 6.70 (s,IH), 6.66-6.64(m, IH), 6.19 (s, 1H), 5.16-5.12 (m, 1H), 2.16-2.11 (m,4H), 1.84 (s, 3H), 1.68 (s, 3H), 1.62 (s, 3H); Minor (Z): 7.13 (d, IH,J=7.5 Hz), 6.76 (d, 1H, J=8 Hz), 6.63 (s, 1H), 6.18(s, IH), 5.10-5.08(m,IH), 2.25-2.121 (m, 4H), 1.86 (s, 3H), 1.66 (s, 3H), 1.61 (s, 3H).¹³C-NMR (CDCl₃, 125 MHz): 155.22 (C), 140.41 (C), 139.43 (C), 131.90(CH), 129.25 (CH), 125.39(C), 124.63 (CH), 121.57 (CH), 115.05 (CH),113.05 (CH), 40.82 (CH₂), 26.77 (CH₂), 25.74 (CH₃), 24.12 (CH₃), 17.95(CH₃).

(E/Z)-5-(2,6-Dimethylhepta-1,5-dienyl)benzene-1,3-diol (3): ¹H-NMR(CDCl₃, 500 MHz): 7.83 (d, IH, J=8 Hz), 6.38 (s, 1H), 6.19 (d, 1H, J=7.5Hz), 6.14 (dd, IH, J=2.5 Hz), 5.16-5.14 (m, 1H), 2.19-2.16 (m, 4H), 1.87(s, 3H), 1.65 (s, 3H), 1.60 (s, 3H); Minor (Z): 6.25 (d, 2H, J=2.5 Hz),6.11 (s, 1H), 5.46 (s, IH), 5.10-5.08(m, IH), 2.23-2.21 (m, 4H), 1.83(s, 3H), 1.65 (s, 3H), 1.58 (s, 3H). ¹³C-NMR (CDCl₃, 125 MHz): 156.65(2C), 141.50 (C), 140.17 (C), 132.03 (C), 125.03 (C), 124.21 (CH),124.08(CH), 108.69 (CH), 100.65 (CH), 40.82 (CH₂), 26.88 (CH₂), 26.80(CH₃), 18.23 (CH₃), 17.93 (CH₃).

(E/Z)-4-(3,7-Dimethylocta-1,6-dienyl)phenol (4): ¹H-NMR (CDCl₃, 500MHz): 6.28 (d, IH, J=2.5 Hz), 6.19 (dd, 1H, J=2.5 & 2.5 Hz), 6.10 (s,IH), 5.47 (s, IH), 5.13-5.11 (m, 1H), 2.16-2.11 (m, 4H), 1.82 (s, 3H),1.67 (s, 3H), 1.61 (s, 3H); Minor (Z): 6.25 (d, 2H, J=2.5 Hz), 6.11 (s,1H), 5.46 (s, IH), 5.10-5.08(m, IH), 2.23-2.21 (m, 4H), 1.83 (s, 3H),1.65 (s, 3H), 1.58 (s, 3H). ¹³C-NMR (CDCl₃, 125 MHz): 159.57 (C), 157.56(C), 142.47 (C), 141.27 (CH), 136.03 (C), 128.31 (C), 126.12 (CH),122.08(CH), 108.69 (CH), 103.57 (CH), 41.28 (CH₂), 27.68 (CH₂), 25.80(CH₃), 18.63 (CH₃), 17.69 (CH₃).

Example 2: General and Specific Methods for the Synthesis of Compoundsof Formula II

Compounds of Formula II were prepared generally as set forth in Scheme2, using a substituted bromobenzene as R for purposes of illustration.Briefly, the 1,6-dienes compounds of Formula II were prepared byGrignard addition reaction from the corresponding Grignard reagents withappropriate aldehyde. The Grignard reagents which was prepared withactivated Mg turnings from the corresponding aryl bromide. Then thecoupled product was treated with POCl₃ for dehydration reaction followedby demethylation reaction with MeMgI to get the desired phenol dienes.

Representative Procedure for Scheme 2: Synthesis of(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5):

General/Typical Procedure for Grignard addition reaction: 4-Bromoanisole(11.2 g. 60 mmol) in THF (60 ml) was added dropwise to magnesiumturnings (1.9 g, 80 mmol) and iodine (a pinch) in THF (10 mL) inrefluxing condition in argon media. After completing the addition, thereaction mixture was continued to reflux for another hour. Then theGrignard reagent was allowed to cool down to room temperature. TheGrignard reagent was then added to a stirred solution of2,6-Dimethyl-5-heptenal (6.4 g, 45 mmol) in THF (50 mL) at 0° C. inargon media and allowed to reach room temperature and continue stirringadditional 3 h. After stirring at room temperature for 3 h, the reactionis complete. The reaction mixture was then cooled down at 0° C. andquenched with ammonium chloride, extracted with ethyl acetate, washedwith brine and dried over anhydrous Na₂SO₄, filtered and concentrated inrotary evaporator and purified by column chromatography to yield (9.5 g,80%) of the coupled product as liquid in 85:15 diastereomeric isomer.

General/Typical Procedure for dehydration reaction: The resultingcoupled product (8.0 g, 31 mmol) was then treated with POCl₃ (7.4g, 48mmol) in pyridine (60 mL) solution and heated to reflux for 3 h. Thereaction mixture was then cooled down and quenched with water, extractedwith ethyl acetate, washed with brine and dried over anhydrous Na₂SO₄,filtered and concentrated in rotary evaporator and purified by columnchromatography to yield (5.7 g, 75%) of the coupled product as a clearliquid as a single isomer.

General/Typical Procedure for demethylation reaction: The resultingalkoxy diene (5.4g, 22 mmol) was dissolved in anhydrous diethyl ether(10 mL) and MeMgI (3M, 8.8 mL, 26.4 mmol) was added to the solution. Thesolvent was removed under reduced pressure, and the residue was heatedunder argon at 130-140° C. for 10 min. The mixture was cooled to rt, andthe reaction was quenched with 10 ml of saturated aqueous NH₄Clsolution, extracted with ethyl acetate, washed with brine and dried overanhydrous Na₂SO₄, filtered and concentrated in rotary evaporator andpurified by column chromatography to get the title compound (5), yield(2.53 g, 50%).

Representative compounds 5-8 were synthesized according to the sameprotocol using appropriate staring materials. Overall yields varied from40-50%.

¹H-NMR (CDCl₃, 500 MHz): 7.24 (d, 2H, J=8.5 Hz), 6.77 (d, 2H, J=8.5 Hz),6.27(d, IH, J=16 Hz), 5.95 (dd, IH, J=16, 8 Hz), 5.14-5.11 (m, 1H)2.31-2.25 (m, 1H), 2.03-1.98 (m, 2H), 1.69 (s, 3H), 1.60 (s, 3H),1.43-1.38 (m, 2H), 1.08 (d, 3H, J=6.5Hz). ¹³C-NMR (CDCl₃, 125 MHz):154.81(C), 134.73 (CH), 131.48 (C), 130.96 (C), 128.53 (CH), 127.65(CH), 127.86 (CH), 115.65(CH), 115.60 (CH), 37.42 (CH), 36.94 (CH₂),26.07 (CH₂), 25.91 (CH₃), 20.92 (CH₃), 17.91 (CH₃).

(E)-4-(3,7-Dimethylocta-1,6-dienyl) benzene-1,3-diol (6)

¹H-NMR (MeOD, 500 MHz): 7.15(d, IH, J=10 Hz), 6.51 (d, IH, J=19 Hz),6.26(s, IH), 6.24 (d, IH, J=10 Hz), 5.89 (dd, IH, J=19, 10 Hz),5.14-5.11 (m, 1H) 2.24-2.21 (m, 1H), 2.03-1.99 (m, 2H), 1.66 (s, 3H),1.59 (s, 3H), 1.40-1.35 (m, 2H), 1.05 (d, 3H, J=5Hz).

¹³C-NMR (MeOD, 125 MHz): 158.28(C), 156.34 (C), 134.16 (CH), 131.98 (C),128.03 (CH), 125.90 (CH), 124.36 (CH), 118.41(CH), 108.00 (CH), 38.69(CH), 38.53 (CH₂), 27.00(CH₂), 25.83 (CH₂), 21.52 (CH₃), 17.92 (CH₃).

(E)-5-(3,7-Dimethylocta-1,6-dienyl) benzene-1,3-diol (7)

¹H-NMR (CDCl₃, 500 MHz): 6.66 (d, IH, J=16 Hz), 6.53(S, 1H), 6.34(s,IH), 6.24 (S, IH), 6.06 (dd, IH, J=16, 8 Hz), 5.18-5.11 (m, 1H),2.38-2.26 (M, 1H), 2.15-196 (m, 2H), 1.68 (s, 3H), 1.61 (s, 3H),1.40-1.35 (m, 2H), 1.15 (d, 3H, J=7Hz)

(E)-6-(3,7-Dimethylocta-1,6-dienyl) naphthalene-2-ol (8)

¹H-NMR (CDCl₃, 500 MHz): 7.67 (d, 2H, J=9 Hz), 7.60 (s, 1H), 7.58 (s,1H), 7.53 (d, 1H, J=9 Hz), 7.70 (d, IH, J=9 Hz), 7.45 (d, IH, J=9 Hz),6.45 (d, IH, J=16 Hz), 6.15 (dd, IH, J=16, 8 Hz), 5.15-5.12 (m, 1H),2.36-2.32 (m, 1H), 2.06-2.0 (m, 2H), 1.69 (s, 3H), 1.60 (s, 3H),1.46-1.43 (m, 2H), 1.11 (d, 3H, J=6.5Hz). ¹³C-NMR (CDCl₃, 125 MHz):153.30(C), 136.48 (CH), 133.87 (C), 133.58 (C), 131.54 (C), 129.58 (CH),128.37 (CH), 126.65 (CH), 125.39 (CH), 118.41(CH), 109.63 (CH), 37.38(CH₃), 37.09 (CH₃), 26.07(CH₂), 25.89 (CH₂), 20.87 (CH₃), 17.90 (CH).

The acid derivative, 9 and 10 were synthesized by O-alkylation reactionwith ethyl bromoacetate followed by base catalyzed hydrolysis from thecorresponding phenolic dienes 5 and 6.

The acetamide derivative (11) was synthesized from 6 by O-alkylationreaction with 2-bromoacetamide.

(E)-2-(4-(3,7-Dimethylocta-1,6-dienyl)phenoxy)acetic acid (9)

¹H-NMR (MeOD, 500 MHz): 7.44 (d, 2H, J=8.5 Hz), 6.89 (d, 2H, J=8.5 Hz),6.34(d, IH, J=16 Hz), 6.15 (dd, IH, J=16, 8 Hz), 5.14-5.11 (m, 1H), 4.66(s, 2H) 2.33-2.28 (m, 1H), 2.13-2.08 (m, 2H), 1.67 (s, 3H), 1.58 (s,3H), 1.45-1.38 (m, 2H), 1.11 (d, 3H, J=6.5Hz)

(E)-2,2′-(4-(3,7-Dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10):

¹H-NMR (MeOD, 500 MHz): 7.52(d, IH, J=10 Hz), 6.66(d, IH, J=19 Hz),6.36(s, IH), 6.28 (d, IH, J=10 Hz), 6.01 (dd, IH, J=19, 10 Hz),5.18-5.14 (m, 1H), 4.63 (s, 2H), 4.58 (s, 2H), 2.34-2.21 (m, 1H),2.13-2.08 (m, 2H), 1.76 (s, 3H), 1.69 (s, 3H), 1.40-1.35 (m, 2H), 1.15(d, 3H, J=7Hz).

(E)-2,2′-(4-(3,7-Dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11): ¹H-NMR (MeOD, 500 MHz): 7.98(d, IH, J=8 Hz), 6.76(d, IH, J=16 Hz),6.46(s, IH), 6.38 (d, IH, J=10 Hz), 6.01 (dd, IH, J=16, 10 Hz),5.15-5.11 (m, 1H), 4.68 (s, 2H), 4.48 (s, 2H), 2.37-2.23 (m, 1H),2.16-2.12 (m, 2H), 1.78 (s, 3H), 1.71 (s, 3H), 1.43-1.38 (m, 2H), 1.17(d, 3H, J=6.5Hz).

Compounds (12-14) of Formula II were prepared generally as set forth inScheme 3, using a substituted bromopyridine as R for purposes ofillustration. Briefly, the 1,6-dienes compounds of Formula II wereprepared by Grignard addition reaction from the corresponding Grignardreagents with appropriate aldehyde. The Grignard reagents were preparedfrom the corresponding aryl bromide. Then the coupled product wastreated with POCl₃ to get the desired dienes.

General/Typical Procedure for Grignard addition reaction: Isopropylmagnesium chloride.LiCl complex solutions was added to a solution of4-Bromobenzene (5.6 g. 30 mmol) in THF at 0C to make the correspondingGrignard reagent. 2,6-Dimethyl-5-heptenal (3.2 g, 22.5 mmol) was thenadded to a stirred solution of the Grignard reagent at 0° C. and allowedto reach room temperature and continue stirring additional 3 h. Afterstirring at room temperature for 3 h, the reaction is complete. Thereaction mixture was then cooled down at 0° C. and quenched withammonium chloride, extracted with ethyl acetate, washed with brine anddried over anhydrous Na₂SO₄, filtered and concentrated in rotaryevaporator and purified by column chromatography to yield (4.5 g, 80%)of the coupled product as liquid.

General/Typical Procedure for dehydration reaction: The resultingcoupled product (4.0 g, 16 mmol) was then treated with POCl₃ (3.7g, 24mmol) in pyridine (32 mL) solution and heated to reflux for 3 h. Thereaction mixture was then cooled down and quenched with water, extractedwith ethyl acetate, washed with brine and dried over anhydrous Na₂SO₄,filtered and concentrated in rotary evaporator and purified by columnchromatography to yield (2.8 g, 75%) of the coupled product as liquid.

(E)-3-(3,7-Dimethylocta-1,6-dienyl) pyridine (12): ¹H-NMR (CDCl₃, 500MHz): 8.57 (d, 1 H, J=7 HZ), 8.53 (s, 1H), 7.571 (d, 1H, J=8 Hz), 7.27(dd, 1H, J=7 & 8 Hz), 6.28 (d, 1H, J=16 Hz), 6.13 (dd, IH, J=8 & 16 Hz),5.06-4.94 (m, 1H), 2.03-1.91 (m, 2H), 1.89-1.78 (m, 1H), 1.65 (s, 3H),1.57 (s, 3H), 1.39-1.36 (m, 1H), 0.93 (d, 3H, J=7 Hz). ¹³C-NMR (CDCl₃,125 MHz): 149.80(C), 149.70 (CH), 136.32 (CH), 135.41 (CH), 131.54 (C),127.23 (C), 126.68 (CH), 124.40.41(CH), 110.84 (CH), 37.28 (CH₂),37.03(CH₂), 26.02 (CH₃), 25.88 (CH₃), 20.74 (CH₃), 17.87 (CH).

Representative compounds 13 and 14 were synthesized according to thesame protocol using appropriate staring materials. Overall yields variedfrom 40-50%.

(E)-2-(3,7-Dimethylocta-1,6-dienyl) pyridine (13)

¹H-NMR (CDCl₃, 500 MHz): 8.65 (d, 1 H, J=7 HZ), 8.57-8.53 (m, 1H), 8.02(d, 1H, J=9 Hz), 7.82 (dd, 1H, J=7 & 9 Hz), 6.42 (d, 1H, J=16 Hz), 7.19(dd, IH, J=8 & 16 Hz), 5.10-5.04 (m, 1H), 2.23-2.10 (m, 1H), 2.09-1.89(m, 2H), 1.64 (s, 3H), 1.58 (s, 3H), 1.39-1.36 (m, 2H), 0.95 (d, 3H, J=7Hz).

(E)-5-(3,7-Dimethylocta-1,6-dienyl)-2-methoxypyridine (14)

¹H-NMR (CDCl₃, 500 MHz): 8.026 (s, 1H), 7.58 (d, 1H, J=10 Hz), 6.64 (d,1H, J=9 Hz), 6,23 (d, 1H, J=16 Hz), 5.93 (dd, IH, J=15, 8 Hz), 5.09-5.06(m, 1H), 3.89 (s, 3H), 2.27-2.24 (m, 1H), 1.98-1.94 (m, 2H), 1.65 (s,3H), 1.57 (s, 3H), 1.39-1.36 (m, 2H), 1.04 (d, 3H, J=7 Hz).

¹³C-NMR (CDCl₃, 125 MHz): 163.30(C), 144.99 (CH), 136.32 (CH), 135.41(CH), 131.54 (C), 127.23 (C), 126.68 (CH), 124.40.41(CH), 110.84 (CH),53.54 (CH₃), 37.28 (CH₂), 37.03(CH₂), 26.02 (CH₃), 25.88 (CH₃), 20.74(CH₃), 17.87 (CH).

Example 3: General and Specific Methods for the Synthesis of Compoundsof Formula III

Compounds of Formula III was prepared generally as set forth in Scheme4, using a substituted benzylphosphonate as R for purposes ofillustration. The phosphonate reagents were prepared from thecorresponding benzyl bromide treated with triethyl phosphite followingArbuzov Reaction. Briefly, the 1,7-dienes compounds of Formula III wereprepared by Wittig reaction from the corresponding phosphonate salt withappropriate ketone. Then the coupled olefin product was treated methylmagnesium iodide for demethylation reaction to get the desired phenoldienes.

General/Typical Procedure for synthesis of phosphonate salt by ArbuzovReaction: A solution of p-methoxybenzylbromide (10.5 g, 52.2 mmol) inP(OEt)₃ (25 mL) was refluxed for 5 h followed by removal of bromethaneand excess triethylphosphite by distillation at reduced pressure. Theresidue provided 12.8 g (95%) of product was enough pure for next step.

General/Typical Procedure for Wittig reaction: To a solution of thephosphonium salt of benzyl bromide (5.2 g, 12 rnmol) and ketone inanhydrous DMF (25 mL), NaH was added at 0° C. portion wise. The reactionmixture was allowed to stir OC for 1 h, during which time the mixturedeveloped a red color indicating the formation of ylide. After stirringat room temperature for 3 h, the reaction is complete. The mixture isdiluted with water at OC and the product is extracted with EtOAc. Theorganic layer is washed with saturated aqueous NaHCO₃ and brine thendried over Na2SO₄. The solvent is removed under reduced pressure and theyellow residue was passed through a short bed of silica gel eluting withethyl acetate-hexane (5:95) to yield the coupled product (3.6 g, 92%) ina ratio of (E/Z: 20/80) as a pale yellow oil.

General/Typical Procedure for demethylation reaction: To a solution ofalokoxy diene (7 g, 21.8 mmol) in 10 ml of Et₂O was added a solution ofMeMgI (3M) in Et₂O (10.0 ml, 30 mmol). The solvent was removed underreduced pressure, and the residue was heated under argon at 130-140° C.for 10 min. The mixture was cooled to rt, and the reaction was quenchedwith 10 ml of saturated aqueous NH₄Cl solution. The product wasextracted with EtOAc (3×100 ml). The combined organic phase was washedwith brine and dried over Na₂SO₄. The solvent was removed under reducedpressure, and the crude product was purified by careful columnchromatography (silica gel; AcOEt/hexane 1:10) to afford the titlecompounds Z-isomer (2.6 g) and E-isomer 0.82g respectively.

(Z)-5-(4,8-Dimethylnona-1,7-dienyl) benzene-1,3-diol (15):

¹H-NMR (CDCl₃, 500 MHz): 6.39 (d, 2H, J=2 Hz), 6.32(d, 1H, J=2 Hz),6.19(d, IH, J=10 Hz), 5.63 (dt, IH, J=10 & 5 Hz), 5.31 (bs, 2H),5.11-5.07 (m, 1H), 2.38-2.26 (m, 2H), 2.25-2.18 (m, 2H), 1.58 (s, 3H),1.56 (s, 3H), 1.40-1.30 (m, 1H), 1.20-1.10 (m, 2H), 0.88 (d, 3H,J=7.5Hz).

¹³C-NMR (MeOD, 125 MHz): 157.09(C), 156.70 (C), 132.86 (C), 130.85 (C),129.04 (CH), 124.98 (CH), 108.67 (CH), 105.84(CH), 101.66 (CH), 101.34(CH), 40.59 (CH), 36.93 (CH₂), 36.03 (CH₂), 33.08 (CH₂), 25.94 (CH₃),25.80 (CH₃), 19.72 (CH₃).

(E)-5-(4,8-Dimethylnona-1,7-dienyl) benzene-1,3-diol (16)

¹H-NMR (CDCl₃, 500 MHz): 6.41 (s, 2H), 6.31(s, 1H), 6.23 (d, IH, J=16Hz), 6.18 (dt, IH, J=16 & 5 Hz), 5.31 (bs, 2H), 5.13-5.09 (m, 1H),2.41-2.26 (m, 2H), 2.25-2.18 (m, 2H), 1.58 (s, 3H), 1.56 (s, 3H),1.44-1.38 (m, 1H), 1.18-1.07 (m, 2H), 0.98 (d, 3H, J=7.5 Hz)

The acid derivative, 17 was synthesized by O-alkylation reaction withethyl bromoacetate followed by base catalyzed hydrolysis from thecorresponding phenolic dienes 16.

Example 4: Tyrosinase Assay

Tyrosinase isolated from the mushroom species Agaricus bisporus waspurchased from the Sigma-Aldrich Inc. (Cat # T3824-50KU). The enzyme wasdissolved in the tyrosinase assay buffer (100 mM sodium phosphate, pH6.8) to a concentration 10 U/μl, and stored at ˜70° C. For theexperiments the enzyme was freshly diluted in the assay buffer to aconcentration of 0.2 U/μl. All test compounds were initially dissolvedin 100% DMSO at a concentration of 400 mM. The compounds were furtherdiluted to a concentration of 2 mM in 10% DMSO. 2 mM stock solutions ofthe compounds were then diluted two-fold in tyrosinase assay buffer with10% DMSO to make ten total test concentrations. Tyrosinase substrate,L-DOPA (Sigma-Aldrich Inc, Cat #37830) was dissolved in the tyrosinaseassay buffer to a concentration of 4 mM. This solution was then used asthe four-fold concentrated stock of substrate in the tyrosinase activityassays. Tyrosinase assays were performed in clear-bottom 96-well platesat room temperature. The final volume of the assays was 200 μl per well.100 μl of two-fold concentrated test compounds were mixed with 50 μl of4 mM L-DOPA. The reactions were initiated by adding 50 μl of mushroomtyrosinase (0.2 U/l, 10 U per reaction), and allowed to proceed for 10minutes. Accumulation of colored product was monitored by lightabsorption at 450 nm using a TECAN Genios plate reader. The assays wereperformed in duplicate and covered a concentration range of testcompounds from 1 mM to 1.95 μM. Mean (n=2) absorption of wellscontaining no enzyme was subtracted as a blank. The data was computed aspercentage activity of wells that contained the tyrosinase, but no testcompounds.

FIG. 9 graphically depicts the mushroom tyrosinase inhibition ofcompound 6 in an in vitro enzymatic inhibition assay as described inExample 4. There is defined dose-dependent inhibition of the tyrosinaseenzyme by compound 6 with an IC₅₀ of 20 μM.

Example 5: Murine Melanoma Cell-Based Assays

Selected compounds were then tested for the ability to suppress melaninproduction by the murine melanoma cells B16-F1 as detailed below.

Murine melanoma cells B16-F1 were purchased from the ATCC (Cat #CRL-6323). Cell Titer96 AqueousOne Solution was purchased from Promega(Cat # G3582). 0.2 μm pore size, low protein binding filters werepurchased from PALL Life Sciences. (Cat # PN4454).

Alpha-MSH was purchased from the Sigma Aldrich (Cat # M4135-1MG). Alltissue culture reagents were purchased from VWR (phenol-red-free DMEM,cat #12001-630, L-glutamine, cat #12001-698) and Fisher Scientific(Trypsin-EDTA, cat #25-200-056).

The B16-F1 cells were maintained in cell growth media (DMEM/High Glucosesupplemented with glutamine, 10% fetal bovine serum, 50 units/mlpenicillin, and 50 units/mL of streptomycin) at 37° C. in a humidifiedatmosphere of 95% air and 5% CO₂.

All test compounds were initially dissolved in 100% DMSO at aconcentration of 400 mM. Then, 6 μL of 400 mM test compounds were addedto 1.2 mL of the cell growth media giving a final concentration of 2 mMfor the test compound and concentration of 0.5% for DMSO. The compoundswere centrifuged for 1 h at 20,000×g. Supernatants (1 mL) were collectedand filtered through sterile 0.2 μm filters. The compounds were seriallydiluted in two-fold increments in the sterile cell growth mediasupplemented with 0.5% DMSO, thus keeping the concentration of DMSOconstant for all samples. These serially diluted compounds weresubsequently used as two-fold concentrated stock solutions in themelanin production and cell viability assays. Equal volumes of 2×compounds were mixed with media containing 2 nM α-MSH to give a finalconcentration of 1 nM α-MSH, 0.5% DMSO, and 1× concentration of testcompounds.

B16-F1 cells were seeded into the wells of clear-bottom 24-well platesat 50,000 cells per well, in 0.5 mL of cell growth media. On thefollowing day, 0.5 mL of freshly prepared test compounds containingα-MSH were added to the wells. The cells were maintained at 37° C. in ahumidified atmosphere of 95% air and 5% CO₂ for 48 hours. At the end ofthe incubation period, melanin-containing conditioned media was removedfrom the cells and transferred to another plate. To measure melanincontent the light absorbance of conditioned media was taken at 492 nmusing a TECAN Genios plate reader.

Viability of cells was measured using standard tetrazolium reductionassay based on redox potential of live cells. Cells were seeded in aclear-bottom 96-well plate in RPMI 1640 media with Glutamax (FisherScientific, cat #61870036) at a density of 5,000 cells/well. Cells weretreated with test compounds dissolved in 100 μL RPMI 1640 media andincubated for 48 hours at 37° C. in a humidified atmosphere of 95% airand 5% CO₂.

After incubation, 20 μL of Aqueous One Solution were added to each welland the plate was returned to the incubator for 30 minutes. Conversionof tetrazolium was monitored by measuring absorbance of cell wells at492 nm using a TECAN Genios plate reader.

Results

The results of the representative experiments are summarized in FIGS.2-8. More than 90% percent of the melanin produced by cultured melanomacells is found in extra-cellular media. Therefore, at the end of theexperiment melanin-containing media was collected and relative amountsof melanin were determined by absorption at 492 nm. Viability of cellswas determined by a commonly used colorimetric procedure that is basedon conversion of the tetrazolium compounds to colored formazan products(using Promega's CellTiter96 AqueousOne assay). Dehydrogenase enzymes inmetabolically active cells accomplish this conversion, and the amount offormazan product is directly proportional to the number of living cellsin culture. Mean (n=2) absorption of wells containing no cells wassubtracted as blanks. The results were computed as percent of wells thatcontained the cells but no test compounds.

Example 6: Reconstructed Human Skin Studies Materials and Methods

The skin whitening effects of test compounds were studied using areconstructed skin model, Melanoderm™ provided by MatTek Corp. (Ashland,Mass.) according to the manufacturer's specifications. Briefly, normalhuman epidermal keratinocytes and normal human melanocytes derived fromdark skin donors were co-cultured on a surface of collagen-coatedmembrane to form multi-layered, highly differentiated skin tissue(MEL-300-B). The tissues were maintained in the CO₂, incubator at 37° C.The apical surfaces of the reconstructed skin (9 mm in diameter) wereexposed to air whereas the bottom surfaces remained in contact with 5 mLof maintenance medium, containing skin differentiating factors(EPI-100-NNM-113). Test compounds were formulated in 80% propyleneglycol as follows: 10 mg of each test compound was dissolved in DMSO anddiluted with 80% propylene glycol (1,2-propanediol, Sigma-Aldrich) tostock concentrations. The compounds were then sterilized by passingthrough 0.2 um filter and diluted in sterile water/propylene glycol tofinal test concentrations in 0.5% DMSO, 80% propylene glycol. Inaddition, the following controls were used: 80% propylene glycol with0.5% DMSO, and 1% kojic acid in 80% propylene glycol.

‘Test compounds were applied to the apical surface of the tissues asfollows: 25 μl of each test compound, 25 μl of 80% propylene glycol(vehicle control), and 25 μl of 1% kojic acid (positive control). Thesamples were reapplied every other day for 14 days. All the samples weretested in duplicate. At the end of the experiment microscopic imageswere taken.

Results

The potential skin-whitening properties of test compounds were exploredin a reconstructed skin model. The model consists of normal,human-derived epidermal keratinocytes and melanocytes, which have beenco-cultured to form a multilayered, highly differentiated humanepidermis. In this study the melanocytes were obtained from a highlypigmented donor.

Different concentrations of test compounds, 80% propylene glycol (thevehicle control), or 1% kojic acid (positive control) were repeatedlyapplied topically on the surface of the reconstructed skin for 15 days.Two of the test compounds, namely, compound #1, and compound #6exhibited significant whitening effects on skin melanocytes, withoutcausing any detectable alterations of cell morphology (FIG. 11B). Ofthem, compound #1 and #6 exhibited the greatest effect with significantwhitening of melanocytes observed as early as 3 days after the beginningof the experiment (data not shown). Photographs of skin specimen takenafter 15 days of the experiment show significant dose-dependentwhitening effects on melanocytes, which appear on photographs as darkdendritic cells.

The compound #1 and #5 also exhibited the greatest effect onpropionibacterium (p-acnes) (MIC/MBC; <3.9 ppm) as well as inhibition ofproinflammatory cytokines in low micro molar range.

FIG. 10A depicts the melanin inhibition of compound 1 on reconstructedskin prepared as described in Example 6. The reconstructed skin wasgrown at the air-liquid interface, making it possible to mimic topicalapplication of skin whitening agents. The reconstructed skin containedboth keratinocytes and melanocytes.

FIG. 10B depicts photographically the results of the reconstructed skinstudies utilizing compound 1 as described in Example 6. Photographs ofskin specimen taken after 14 days of the experiment show significantwhitening effects on melanocytes, which appear on photographs as darkdendritic cells.

FIG. 11A depicts the melanin inhibition of compound 4 on reconstructedskin prepared as described in Example 6. The reconstructed skin wasgrown at the air-liquid interface, making it possible to mimic topicalapplication of skin whitening agents. The reconstructed skin containedboth keratinocytes and melanocytes. At 0.05%, compound 4 showed sometoxicity.

FIG. 11B depicts photographically the results of the reconstructed skinstudies utilizing compound 4 as described in Example 6. Photographs ofskin specimen taken after 14 days of the experiment show significantwhitening effects on melanocytes, which appear on photographs as darkdendritic cells. At 0.05%, compound 4 showed some toxicity.

FIG. 12A depicts the melanin inhibition of compound 6 on reconstructedskin prepared as described in Example 6. The reconstructed skin wasgrown at the air-liquid interface, making it possible to mimic topicalapplication of skin whitening agents. The reconstructed skin containedboth keratinocytes and melanocytes.

FIG. 12B depicts photographically the results of the reconstructed skinstudies utilizing compound 6 as described in Example 6. Photographs ofskin specimen taken after 14 days of the experiment show significantwhitening effects on melanocytes, which appear on photographs as darkdendritic cells.

FIG. 13A depicts the melanin inhibition of compound 7 on reconstructedskin prepared as described in Example 6. The reconstructed skin wasgrown at the air-liquid interface, making it possible to mimic topicalapplication of skin whitening agents. The reconstructed skin containedboth keratinocytes and melanocytes. At 0.05%, compound 7 showed sometoxicity.

FIG. 13B depicts photographically the results of the reconstructed skinstudies utilizing compound 7 as described in Example 6. Photographs ofskin specimen taken after 14 days of the experiment show significantwhitening effects on melanocytes, which appear on photographs as darkdendritic cells. At 0.05%, compound 7 showed some toxicity.

FIG. 14A depicts the melanin inhibition of compound 8 on reconstructedskin prepared as described in Example 6. The reconstructed skin wasgrown at the air-liquid interface, making it possible to mimic topicalapplication of skin whitening agents. The reconstructed skin containedboth keratinocytes and melanocytes. At 0.05%, compound 8 showed sometoxicity.

FIG. 15A depicts the melanin inhibition of compound 12 on reconstructedskin prepared as described in Example 6. The reconstructed skin wasgrown at the air-liquid interface, making it possible to mimic topicalapplication of skin whitening agents. The reconstructed skin containedboth keratinocytes and melanocytes. At 0.05%, compound 12 showed sometoxicity.

FIG. 15B depicts photographically the results of the reconstructed skinstudies utilizing compound 12 as described in Example 6. Photographs ofskin specimen taken after 14 days of the experiment show significantwhitening effects on melanocytes, which appear on photographs as darkdendritic cells. At 0.05%, compound 12 showed some toxicity.

FIG. 16A depicts the melanin inhibition of compound 15 on reconstructedskin prepared as described in Example 6. The reconstructed skin wasgrown at the air-liquid interface, making it possible to mimic topicalapplication of skin whitening agents. The reconstructed skin containedboth keratinocytes and melanocytes. At 0.05%, compound 15 showed sometoxicity.

FIG. 16B depicts photographically the results of the reconstructed skinstudies utilizing compound 15 as described in Example 6. Photographs ofskin specimen taken after 14 days of the experiment show significantwhitening effects on melanocytes, which appear on photographs as darkdendritic cells. At 0.05%, compound 15 showed some toxicity.

Example 7: P-Acne Test

The anti-microbial activity of the tested compounds were evaluated usingpublished methods (Modugno e. al. (1994) Antimicrobial agents andChemotherapy 38: 2362-2368; Misiek et. al. (1973) Antimicrobial agentsand Chemotherapy 3: 40-48. Propionibacterium acnes (ATCC11827) wascultured for 20 hours at 37° C. in Reinforced Clostridal medium. Thetest article and positive control were dissolved in 1% DMSO with anincubation volume of 1 mL. The time of assessment was 1 day. Measurementof turbidity was used as the method of quantification. The compoundswere tested in duplicate at concentrations of 250 ug/mL, 125 ug/mL, 62ug/mL, 31 ug/mL, 16 ug/mL, 8 ug/mL, 4 ug/mL, 2 ug/mL relative topositive control ampicillin at 0.1 ug/mL.

Example 8: Inflammatory Test

Inhibition of COX-1 and COX-2 by tested compounds

In order to screen for compounds that inhibited COX-1 and Cox-2activity, enzymatic inhibition assay kits were purchased from CaymanChemical (cat #701050). Briefly, the compound being examined was treatedagainst a fixed amount of COX-1 and COX-2 enzymes. A cleavable, peroxidechromophore was included in the assay to visualize the peroxidaseactivity of each enzyme in presence of arachidonic acid as cofactor.Typically, assays were performed in 96-well format. Each inhibitor,taken from a 1 M stock solution in 100% DMSO, was tested in duplicate atroom temperature using the following range of concentrations: 1.9, 3.9,7.8, 15.6, 31.2, 62.5, 125, 250, 500, and 1000 μM. To each well, 150 μLof Assay Buffer was added along with 10 μL of Hemin, 10 μL of inhibitordiluted in DMSO and 10 μL of either COX-1 or COX-2 enzyme. The compoundswere incubated for 5 minutes at room temperature, followed by theaddition of 20 μL of Colormietric Substrate solution and 20 μL ofarachidonic acid solution to initiate the reaction. The plate was mixedand incubated for 2 minutes before reading the absorbance at 590 nm. Theinhibitor concentration vs. % of inhibition was plotted and the IC₅₀determined.

Inhibition of 5-Lipoxygenase Tested Compounds

One of the most important pathway involved in the inflammatory responseis produced by non-heme, ion-containing lipoxygenases (5-LOX, 12-LOX and15-LOX) which catalyze the oxidation of fatty acids such as AA toproduce the hydoperoxides 5-, 12- and 15-HEPTE, which are then convertedto leukotrienes. A Lipoxygenase Inhibition Assay was carried out usingcommercial kit from Cayman Chemical (cat #760700, 5-lipoxygenase frompotato, cat #60400). The test article and positive control weredissolved in 1% DMSO. 90 μL of diluted potato lipoxygenase enzyme and 10μL inhibitor were added to a flat-bottom clear 96-well microplate. Theplate was pre-incubated for five minutes at room temperature. Thereaction was initiated by the addition of 10 μL linoleic acid substrate.The plate was then placed on a shaker for 10 minutes at roomtemperature. 100 μL Chromogen solution was added to each well and theplate was shaken again for five minutes. The absorbance was read at 492nm using a TECAN Genios plate reader. The inhibitor concentration vs. %of inhibition was plotted and the IC₅₀ determined.

1. A compound of formula I:

wherein R comprises an aromatic or heteroaromatic ring selected from thegroup consisting of phenyl, naphthyl, biphenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-furanyl, 3-furanyl; wherein R is substituted with 1 to 3moieties (R′, R″, R′″) independently selected from the group consistingof a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group or a hydroxyl group. 2.The compound of claim 1, wherein R is selected from the group consistingof an aromatic or heteroaromatic ring selected from the group consistingof phenyl, naphthyl, biphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-furanyl, 3-furanyl; wherein R is substituted with 1 to 3 moieties (R′,R″, R′″) independently selected from the group consisting of a C₁-C₁₀alkyl group, a C₁-C₁₀ alkoxy group or a hydroxyl group.
 3. The compoundof claim 1, wherein R is selected from the group consisting of1′-(4′-hydroxy)phenyl; 1′-(3′-hydroxy)phenyl;1′-(2′,4′-dihydroxy)phenyl; 1′-(3′,5′-dihydroxy)phenyl with E and Zgeometrical isomer.
 4. The compound of claim 1 selected from the groupconsisting of (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4).
 5. Acompound of formula II:

wherein R comprises an aromatic or heteroaromatic ring selected from thegroup consisting of phenyl, naphthyl, biphenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-furanyl, 3-furanyl; wherein R is substituted with 1 to 3moieties (R′, R″, R′″) independently selected from the group consistingof a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group or a hydroxyl group. 6.The compound of claim 5, wherein R is selected from the group consistingof an aromatic or heteroaromatic ring selected from the group consistingof phenyl, naphthyl, biphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-furanyl, 3-furanyl; wherein R is substituted with 1 to 3 moieties (R′,R″, R′″) independently selected from the group consisting of a C₁-C₁₀alkyl group, a C₁-C₁₀ alkoxy group or a hydroxyl group.
 7. The compoundof claim 4 wherein R is selected from the group consisting of1′-(4′-hydroxy)phenyl; 1′-(2′,4′-dihydroxy)phenyl;1′-(3′,5′-dihydroxy)phenyl; 1′-(4′-hydroxy)naphthyl; 3′-pyridyl;2′-pyridyl; 3′-pyridyl; 1′-(4′-methox)-3′-pyridyl .
 8. The compound ofclaim 4 selected from the group consisting of((E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14).
 9. Acompound of Formula III:

wherein R comprises an aromatic or heteroaromatic ring selected from thegroup consisting of phenyl, naphthyl, biphenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-furanyl, 3-furanyl; wherein R is substituted with 1 to 3moieties (R′, R″, R′″) independently selected from the group consistingof a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group or a hydroxyl group. 10.The compound of claim 9, wherein R is selected from the group consistingof an aromatic or heteroaromatic ring selected from the group consistingof phenyl, naphthyl, biphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-furanyl, 3-furanyl; wherein R is substituted with 1 to 3 moieties (R′,R″, R′″) independently selected from the group consisting of a C₁-C₁₀alkyl group, a C₁-C₁₀ alkoxy group or a hydroxyl group.
 11. The compoundof claim 9, wherein R is selected from the group consisting of1′-(3′,5′-dihydroxy)phenyl with E and Z geometrical isomer.
 12. Thecompound of claim 9, wherein the compound is selected from the groupconsisting of (Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17).
 13. A composition comprising(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.
 14. A methodfor inhibiting the production of melanin comprising administering to asubject in need thereof a composition comprising at least one of thefollowing compounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.
 15. A methodfor preventing and treating diseases and conditions related to theoverproduction or uneven distribution of melanin comprisingadministering to a subject in need thereof an effective amount of acomposition comprising at least one of the following compounds:(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.
 16. A methodfor whitening and/or lightening skin comprising administering to asubject in need thereof a composition comprising at least one of thefollowing compounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.
 17. A methodfor preventing melanin synthesis wherein the symptom, condition,disorder, or disease associated tyrosinase inhibition comprisingadministering to a subject in need thereof an effective amount of acomposition comprising at least one of the following compounds:(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1, 5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.
 18. A methodfor preventing melanin synthesis wherein the symptom, condition,disorder, or disease associated non-tyrosinase inhibition comprisingadministering to a subject in need thereof an effective amount of acomposition comprising at least one of the following compounds:(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1, 5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.
 19. A methodfor preventing and treating diseases wherein the symptom, condition,disorder, or disease associated with free radicals, oxidative stress, UVrays induced skin damages, skin aging, skin inflammatory diseases ordisorders, skin degenerative diseases or disorders comprisingadministering to a subject in need thereof an effective amount of acomposition comprising at least one of the following compounds:(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.
 20. A methodfor inhibit the browning and color changes in fruits, vegetables, juicesand other food products comprising administering a compound comprisingat least one of the following compounds:(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1, 5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.
 21. The methodof claim 17, wherein the diseases and conditions comprise suntan, hyperpigmentation spots caused by skin aging, melasma, liver diseases,thermal burns and topical wounds, skin pigmentation due to inflammatoryconditions caused by fungal, microbial and viral infections, vitiligo,carcinoma, melanoma, as well as other mammalian skin conditions.
 22. Amethod for suppressing the activity of Propionibacterium (p-acnes)comprising administering to a patient in need thereof a compositioncomprising at least one the following compounds:(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide(11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.
 23. A methodfor deactivating the activity of proinflammatory cytokines, such asCOX-1, COX-2, and 5-LOX comprising administering to a patient in needthereof a composition comprising at least one of the followingcompounds: (E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)phenol (1);(E/Z)-3-(2,6-dimethylhepta-1,5-dienyl)phenol (2);(E/Z)-4-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (3);(E/Z)-5-(2,6-dimethylhepta-1,5-dienyl)benzene-1,3-diol (4);(E)-4-(3,7-dimethylocta-1,6-dienyl)phenol (5);(E)-4-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (6);(E)-5-(3,7-dimethylocta-1,6-dienyl) benzene-1,3-diol (7);E)-6-(3,7-dimethylocta-1,6-dienyl) naphthalene-2-ol (8);(E)-2-(4-(3,7-dimethylocta-1,6-dienyl)phenoxy)acetic acid (9);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (10);(E)-2,2′-(4-(3,7-dimethylocta-1,6-dienyl)-1,3-phenylene)bis(oxy)diacetamide (11); (E)-3-(3,7-dimethylocta-1,6-dienyl) pyridine (12);(E)-2-(3,7-dimethylocta-1,6-dienyl) pyridine (13),(E)-5-(3,7-dimethylocta-1,6-dienyl)-2-methoxypyridine (14);(Z)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (15);(E)-5-(4,8-dimethylnona-1,7-dienyl) benzene-1,3-diol (16);(E)-2,2′-(5-(4,8-dimethylnona-1,7-dienyl)-1,3-phenylene)bis(oxy)diaceticacid (17) or a pharmaceutically acceptable salt thereof.
 24. The methodof claim 19, wherein said diseases and conditions are selected from thegroup consisting of suntan, hyper pigmentation spots caused by skinaging, melasma, liver diseases, thermal burns and topical wounds, skinpigmentation due to inflammatory conditions caused by fungal, microbialand viral infections, vitiligo, carcinoma, melanoma, as well as othermammalian skin conditions.
 25. The method of claim 24, wherein the postinflammatory hyperpigmentation (PIH) is derived from acne, atopicdermatitis, allergic contact dermatitis, incontinent pigmentation,lichen planus, lupus erythematosus, morphea, mechanical trauma, ionizingor nonionizing radiation, burns, laser or drug therapies, skin infectionor combinations thereof.